1. In this randomized controlled trial, among patients with primary biliary cholangitis (PBC) who had had inadequate response to ursodeoxycholic acid, seladelpar was superior to placebo in achieving biochemical response and symptomatic management.

2. Seladelpar had an acceptable safety profile, with similar rates of adverse events to a placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: PBC is a rare liver disease caused by inflammation of intrahepatic bile ducts, leading to bile accumulation, biliary fibrosis, and eventually cirrhosis and liver failure. Ursodeoxycholic acid is the first-line treatment for PBC, but many patients have inadequate response, with persistently high alkaline phosphatase (ALP) or bilirubin levels. Seladelpar is a selective agonist of peroxisome proliferator-activated receptor delta (PPARd), which is key in several pathophysiologic pathways of PBC. The current phase three trial evaluated the efficacy and safety of seladelpar for patients with PBC who had had inadequate response to ursodeoxycholic acid. By month 12, patients in the seladelpar group had a significantly higher rate of biochemical response, defined by ALP and bilirubin levels, compared to the placebo group. Significantly higher proportions of seladelpar recipients also showed normalization of the ALP level and reduction in pruritus than placebo. Seladelpar was associated with higher rates of headache, gastrointestinal upset, and coronavirus disease 2019 (COVID-19), all of which were mild and did not result in discontinuation. Although these were early results with limited safety data, the trial demonstrated the potential of seladelpar as a therapy for PBC.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This study was a randomized controlled trial to evaluate seladelpar to treating PBC. Patients between 18 and 75 years of age with PBC, adequate renal function, and normal platelet count, treated with ursodeoxycholic acid for at least 12 months, or had unacceptable side effects with the medication were eligible for inclusion. Exclusion criteria included advanced PBC, hepatic decompensation, and other concomitant chronic liver disease. In total, 193 patients were randomized 2:1 to receive oral seladelpar 10mg or placebo daily. The primary outcome was a biochemical response, defined as an ALP level less than 1.67 times the ULN with a reduction of ≥15% from baseline and a normal total bilirubin level by 12 months. Secondary outcomes included normalization of ALP level at month 12, change from baseline in the score of pruritus numerical rating scale (NRS) by six months in patients with a baseline score of ≥4/10 (moderate itch), and quality of life assessment. Overall, at 12 months, significantly more patients in the seladelpar group (61.7%) demonstrated a biochemical response compared to the placebo group (20.0%) (difference, 41.7 percentage points; 95% Confidence Interval [CI], 27.7 to 53.4; p<0.001). Additionally, ALP was normalized in 25.0% of seladelpar recipients compared to none in those receiving placebo (difference, 25.0 percentage points; 95% CI, 18.3 to 33.2; p<0.001). At six months, among patients with moderate itch at baseline, seladelpar resulted in a greater reduction in pruritis NRS than placebo (p=0.005). Although the overall rates of adverse events were comparable between the two groups, seladelpar was associated with higher incidences of COVID-19, headache, and gastrointestinal upset. No serious adverse events were deemed to be related to seladelpar. These results demonstrated the efficacy of seladelpar as a second-line therapy to achieve biochemical response and symptomatic relief for patients with PBC.

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